Accelerating progress in the fight against cancer requires a new paradigm where we validate the right pathways, target these pathways with the right drugs, and test them in the right patients. Development of novel targeted agents requires novel approaches, as traditional study designs for proof-of-concept phase II studies are increasingly inadequate. Likewise, the presence of a drug target may not be sufficient for response or survival benefit. Specific genetic alterations may occur in the context of other mutations, environmental and microenvironment differences. The current application titled Southwest Early Clinical Trial - Phase 2 Consortium (SECT-P2C) will expand the scope of our NCI UM1-funded Southwest Early Clinical Trials (SECT) Consortium to include the long- standing N01-supported Phase 2 program at MD Anderson Cancer Center, and the collaborative Phase 2 program at the University of Colorado Cancer Center. We hypothesize that the optimal phase II development of novel agents requires: 1) testing within a molecularly and genomically profiled, disease-specific population; 2) use of appropriately tailored study designs for proof-of-concept studies; 3) where appropriate, biomarker-driven multi-cohort screening studies to assess for initial signals of activity; and 4) evaluation of biomarkers that ae associated with response or resistance. We are uniquely qualified and positioned to contribute to the goals of the overall NCI clinical trial program through the execution of the following Specific Aims: 1. To conduct phase II studies, in an efficient and collaborative manner, and assess efficacy and safety of new agents or combinations in molecularly profiled, disease-specific populations: 2. To molecularly and genomically profile tumor and patient (host) tissues, including germline variants and assessment of microenvironment and immune profiles, to optimize selection of potentially relevant therapies. 3. To develop clinically relevant markers associated with response or resistance: 4. To lead and participate in collaborative research in ETCTN through active project team participation, clinical research design and protocol development, authorship/co-authorship of ETCTN publications, and attendance at ETCTN meetings. 5. To mentor junior faculty, trainees and research personnel in the leadership, conduct, analysis, and reporting of ETCTN and other early phase clinical trials.